Method of manufacturing dialkylamino-1,3,4-oxadiazoles and 1,3,4-thiadiazoles

ABSTRACT

5-SUBSTITUTED TETRAZOLES ARE REACTED WITH N,N-DIALKYL CARBAMYL CHLORIDES OR CORRESPONDING THIOCARBAMYL CHLORIDES AND THE REACTION PRODUCTS ARE HEATED TO PRODUCE 2DIALKYLAMINO-5-SUBSTITUTED-1,3,4-OXADIAZOLES AND THIADIA: ZOLES BY DECOMPOSITION AND MOLECULAR REARRANGEMENT, THE PRODUCTS ARE USEFUL AS SELECTIVE HERBICIDES.

United States Patent 3,790,588 METHOD OF MANUFACTURING DIALKYL- AMINO 1,3,4 OXADIAZOLES AND 1,3,4- TI-IIADIAZOLES Norman A. Dahle, Mission, Kans., assignor to Gulf Research and Development Company, Pittsburgh, Pa. No Drawing. Filed Oct. 24, 1969, Ser. No. 869,385 Int. Cl. C07d 85/54, 91/62 US. Cl. 260-3063 D 6 Claims ABSTRACT OF THE DISCLOSURE S-substituted tetrazoles are reacted with N,N-dialkyl carbamyl chlorides or corresponding thiocarbamyl chlorides and the reaction products are heated to produce 2- dialkylamino-S-substituted-1,3,4-oxadiazoles and thiadiazoles by decomposition and molecular rearrangement. The products are useful as selective herbicides.

DESCRIPTION OF INVENTION This invention is a new method for the synthesis of 2 dialkylamino-S-substituted-1,3,4-oxadiazoles and thiadiazoles of the general structural formulas:

Ari LN and Ari LN A procedure for synthesis of 2,5-dialkyl-1,3,4-oxadiazoles developed by R. Huisgen et al. utilizes the reaction of a S-substituted tetrazole (2) with an acid anhydride or halide (3) to give the substituted-2-acyl-2H-tetrazole (4) which rearranges on heating to the corresponding 2, 5 -disubstituted oxadiazole (5) according to the following scheme:

(R=alkyl or aryl; R.=methyl or ethyl.) I have discovered that the carboxamide derivative (6), readily loses nitrogen 3,790,588 Patented Feb. 5, 1974 and rearranges when heated at -130 C. to give the members of the oxadiazole series represented by the general structural Formula 1. Alternatively, a thiocarbamyl tetrazole is believed to rearrange to the corresponding thiadiazole. However, it is more convenient to continue heating after mixing the thiocarbamyl chloride with the S-aryltetrazole, obtaining the thiadiazole directly, Without attempting to isolate a thiocarbamyltetrazole intermediate compound.

The structural formulas of the intermediate tetrazoles and oxadiazoles which appear herein are consistent with the disclosures in the literature, particuarly by Huisgen and coworkers, in the following references:

(a) R. Huisgen, Agnew. Chem., 70, 359 (1960);

b) R. Huisgen, J. Sauer, H. J. Sturm, and I. H. Markgraf Ben, 93, 2106 (1960);

(c) I. Sauer, R. Huisgen, and H. J. Sturm Tetrahedron (d) R. Huisgen, H. I. Sturm, and M. Seidel, Ber. 93,

(e) R. Huisgen, H. I. Sturm, and M. Seidel, Ber. 94,

(f) R. Huisgen, J. Sauer, and M. Seidel, Ber. 94, 2503 The known oxadiazole compounds prepared by the method of this invention have melting points which are substantially identical to the melting points of the same compounds disclosed in the literature and prepared by an unambiguous route. (See CA: 64 P5106f, Fr. M3573.)

The tetrazole starting materials employed in the following illustrative procedures were prepared by the method of W. G. Finnegan, R. A. Henry and R. Lofquist which utilizes the reaction of arylnitriles with a mixture of ammonium chloride and sodium azide in dimethyl formamide containing a catalytic amount of lithium chloride. (W. G. Finnegan, R. A. Henry, and R. Lofquist, J. Am Chem. Soc., 80, 3908 (1958), and US. Pat. 2,977,372.)

ILLUSTRATIVE PROCEDURES 5-aryl-2-dialkylcarbamyl-2T-tetrazoles The following general procedure was utilized in the preparation of these compounds. To a stirred solution of the appropriate tetrazole dissolved in a minimum volume of pyridine was added dropwise the dialkyl carbamyl chloride, keeping the temperature below 30' by cooling the reaction flask in an ice bath. The reaction mixture, after standing overnight, was cooled in an ice bath and diluted with water. The insoluble material was collected by vacuum filtration and allowed to dry in air. A portion of the crude product was purified for use and for combustion analysis by dissolving it in ethyl acetate, at room temperature, filtering the resulting solution and precipitating the product with hexane. The nuclear magnetic resonance spectrum of the product showed a characteristic broad peak for the hydrogens attached to the carbon adjacent to the carboxamide nitrogen. The infrared spectrum 'of the product exhibited a peak at 5.8 111p.

2-aryl-5-dialkylamino-1,3,4-oxadiazoles The following is a description of the general procedure of this invention for the preparation of the aryl dialkylamino oxadiazoles. The crude product resulting from the treatment of a tetrazole with a dialkylcarbamyl chloride was placed in a test tube (30 x 7.5 cm.) equipped -with a magnetic stirrer and immersed in an oil bath. The

temperature was slowly increased until the solid melted.

3 If the melting point of the starting material was over 100 C. the bath temperature was held at 80 C. for 1-2 hours prior to increasing the temperature to the melting point. The temperature of the oil bath was slowly raised to l20-30 and maintained until the evolution of nitrogen ceased. The tube and its contents were allowed to cool to room temperature and the resulting product was purified by distillation or recrystallization from a suitable solvent. The infrared spectrum of the product showed the absence of a carbamyl absorption in the 5.8 mm. region and the appearance of a strong band in the 6.2 mm. region. The nuclear magnetic resonance spectrum exhibited a sharp absorption for the hydrogen atoms on the carbon atoms adjacent to the nitrogen.

Preparation of 2-aryl-5-dialkylamino- 1,3,4-oxadiazoles hydrochlorides The oxadiazole was dissolved in a small volume of ether and hydrogen chloride was bubbled through the solution until the precipitation was complete. The insoluble material was separated and used without further purification.

4 l 2-aryl-5-dimethylamino- (diethylamino)- 1,3,4-thiadiazoles The preparation of Z-dimethylamino-S-phenyl-1,3,4- thiadiazole will serve as an illustration of the general procedure employed to prepare these compounds.

A stirred mixture of 14.6 g. ((0.1 mole) of 5-phenyltetrazole and 13.5 g. (0.11 mole) of dimethylthiocarbamyl chloride in 150 ml. of 1,2-dimethoxyethane was heated at reflux for 18 hours. The liquid in the mixture was then evaporated to dryness and the resulting residue was allowed to stir with 150 ml. of 5% sodium hydroxide for 4 hours. The insoluble material was separated, Washed well with water and recrystallized from ethyl acetate to give 8.3 g. (43%): M.P. 97-99. The infrared spectrum shows a strong band at 6.5 g., a feature characteristic of this group of compounds.

Structural formulas and properties of compounds prepared by the method of this invention appear in the following tables. I

2-ARYL-5-DIALKYLAMINO-1,3,4-OXADIAZOLES BIN g Ar Analysis N M P. 0.) Calculated Found or B.P. A; R C./mm.) C H N C H N Ph Mn 8 N 0 analysis Ph EL 118-20/0 66. 34 6. 96 19. 34 66. 6. 98 19. 35 o-ClPh Mb 70-7 53.70 4.50 18.78 53 54 4.30 18.20, o-OlPh Et 150-6/0. 1 57. 5. 60 16. 69 57. 06 5. 99 17. o-ClPh Hydrochloride 167-7 50.01 5.24 14.58 49.97 5.40 14 m-ClPh MR 105 No analysis m-ClPh Et- 148-52/0. 1 57. 25 5. 16. 69 57. 16 5. 67 16. 60 p-ClPh Me 140-41 53. 70 4. 50 18. 78 54. 03 4. 83 17.55 o-CtPh Et. 92. 3 57. 25 5. 60 16. 69 57. 49 5. 30 16. 60 o-OlPh-.. Hydrochloride- 125-9 No analysis 2 4-di-C1Ph E1: 146-8/0 05 50. 36 4. 57 14. 68 50. 29 4.89 14. 78 o-MePh Er 124-30/0.1 67. 50 7. 40 18. 16 67. 78 7. 18. 85 o-MePh Hydrnr-hlnri n 137-42 58. 31 6. 77 15. 69 58. 31 6. 80 15. 68 o-MePh Mn 57-8 65. O0 6. 44 20. 67 64. 93 6. 47 20. 75 m-MePh Me hydrochloride.-- 215-17 55. 11 5. 88 17. 53 55. 01 6. 26 17. 30 m-MePh Me Y -71 65. 00 6. 44 20. 67 64.50 6. 36 20. m-MePh Er 128-32/0. 1 67. 50 7. 40 18. 16 67. 12 7.60 19. 70 m-MePh Hydroehloride--. 173-5 58. 31 6. 77 15. 69 58.27 6. 55 15. 90 p-MePh Mn 73.4 65. 00 6. 44 20. 67 64. 88 6. 19 20. 75 o-MePh Et 54. 6 67. 50 7. 40 18. 16 67. 51 7. 46 16. 08 2,4-di-MePh Me 102-4 66. 34 6. 96 19. 34 60.40 6; 75 19. 15 2 ,4-di-MePh- 68. 54 7. 17. 12 68. 78 7. 79 17. 00 2,4-di-MePh. 1-3 59. 67 7. 1:5 14.91 59. 60 6.94 15.00 3,4-di-MePh. 66. 34 6. 96 19. 34 66. 14 6. 18. 70 2 4,6t1i-MePh- 69. 46 8. 16 16. 20 69. 83 8. 04 16.05 o-MeOPh 60. 26 5. 97 19. 16 60. 39 6. 02 19. 29 o-MeOPh a 63. 13 6.92 16. 99 63. 35 6.73 18. 3,4-di-MeOPh--.. Me 109-10 57. 82 6. 06 16. 85 57. 62 6. 04 14. 30 3,5-di-Me0Ph Me. 111-12 57.82 6.06 16.83 57.51 6.07 16.74 p-FPh Me 101-3 57. 96 4. 86 20. 27 58. 26 4. 72 19. p-FPh 61. 5. 99 17. 86 61. 10 5. 89 17. 60 p-EtzNPh- 8-9 7. 74 21. 52 64. 89 7. 72 70 p-MezNPh- No analysis; NMR consistent p-NOiPh Et- 7-9 54. 95 5. 38 21. 36 54. 94 5. 68 21. 44 p-NOaPh Ma 147-9 51. 28 4. 30 23. 92 50. 95 4. 14 23. 91 a-Nephthyl Me 112-13 70. 27 5. 47 17. 56 70.28 -5. 32 17. 76

Do- E 95-7 71.88 6. 40 15.72 71. 65 6.32 16.06 2-4y14d 1 Me 114-15 56. 83 5. 29 29. 45 56. 94 5. 20 28. 90 6- e-2-pyridy1 Me- 113-15 58. 80 5. 92 27. 43 58. 56 5. 93 28. 80 3,5-d1-N02Ph.--- e.. 158-9 43. 01 3.24 25. 08 42. 12 3. 10 24. 93 3,5-d1-N02Ph Et -12 46. 90 4. 26 22. 79 39. 71 3.34 19.34 p-Me;NCONHPh Et 169-71 59.38 6. 97 23. 08 58. 28 6. 61 23. 23 p-NH Ph Et 107-8 62. 04 6. 94 24. 12 59. 90 6. 74 24. 05

Me. 247-8 36. 16 3.94 16. 86 36. 80 4. 14 I 17.03 Me- 4-pyrtdv1 Me 121-3 56. 83 5. 29 29. 45 35. 91 5. 05 30. 31 3,4-di-C1Ph Et 114-15 50.36 4. 57 14. 68 49. 75 4.43 14. 72 -2 46. 53 3. 51 16. 28 46. 26 3. 20 16. 45 89-91 54. 95 5. 38 21. 36 54. 79 5. 41 22. 08 136-7 51.28. 4.30 23.92 0 50.78 4.23 24.23 198-4 59. 07 7. 62 21. 19 62. 10 6. 94 20. 24 220-2 59. 98 6. 19 21. 52 59. 27 6. 12 22. 25 104-5 55. 58 5. 08 17. 68 55. 22 5. 22 18. 10 3-C1-4-MePh 73-4 58. 75 6. 06 15. 81 59. 16 5. 97 15. 97 p-OHPh Et. -7 61. 78 6. 48 18.01 61. 6.30 18. 30 4-Et NC0r35-d1-BrPh-" Et 131-3 41. 65 4. 52 11. 43 41. 86 4. 69 11. 45

STRUCTURE AND PHYSICAL PROPERTIES OF 5-ARYL-DIALKYLAMINO-1,3,4-THIADIAZOLES S RIN Ar I 1 Analysis Calculated Found .1. C.) or

Ar R B.P. CJmm.) C H 01 N S C H Cl N S Hhlowphenyl Methyl 7H7 {-?.f3 i? l?'f?--.Y:f?.--?fl- 2313 iii 121%? 312% 13:32 148-153/0. 5 0. 05 53. 82 5. 27 13. 23 11. 97 56. 5. 54 12. 51 14. 60 11. 30

148-50 Not sted Not tested 149-50 50. 10 4. 14. 17. 52 13. 37 49. 94 3. 93 17. 60 13. 70 14. 90 201-02 doc. 42. 56 3. 92 25. 12 17. 01 11. 36 43. 28 4. 12 25. 30 15. 11. 50 hyl 50. 10 4. 20 14. 78 17. 52 13. 37 49. 91 3. 94 14. 85 17. 40 13. 30 Methyl HCl. 214-15 dee. 43. 48 4. 01 25. 67 15. 21 11. 60 43. 10 3. 96 25. 80 14. 98 11. 31 yl 119-120 53. 82 5. 27 13. 23 15. 69 11. 97 54. 00 5. 28 13. 22 15. 57 11. 95 180-82 47. 35 4. 97 23 29 13. 11 10. 54 47. 24 5. 23 23. 90 13. 60 10. 52 56-57 60. 24 5. 97 19. 62 14. 68 60. 27 6. 24 19. 62 14. 82 160/0. 2-0 25 63. 12 6. 92 16. 98 12. 96 62. 83 7. 11 16. 80 13. 10 D0 90-120 dec 55. 01 6. 39 12. 48 14. 80 11. 29 52. 32 5. 91 12. 60 11. 51 3-methy1phenyL- Methyl 84-85 60. 24 5. 97 19. 62 14.62 60. 35 5. 85 19. 16 14. 60 D0 Methyl HCL 227-29 dec. 51. 65 5. 51 13. 86 16. 42 12. 57 51. 87 5. 85 92 12. 55 Do E yl 156-62/0.225 mm. 63. 12 6. 92 16. 98 12. 96 63. 31 7. 01 69 13. 05

o Ethyl H01 140-43 55. 01 6. 39 12. 48 14. 81 1 1. 29 56. 78 6. 21 40 11. 00 4-methylphenyl ethyl 140-41 60. 24 5. 97 19. 62 14. 62 60. 25 5. 89 14. 65

o Methyl HCl 213-15 51. 65 5. 51 13. 86 16. 42 12. 53 51. 22 5. 38 12. 72

Do thyl 252-53 63. 12 6. 92 16. 98 12. 96 63. 34 7. 10 12. 81 2,4-dl1nethylphenyl Methyl 86.87 61. 77 6. 47 18, 00 13. 74 62. 10 6. 33 18. 13. 65

Do Methyl HCl 223-24 dec. 53. 42 5. 97 13. 14 15. 57 11. 88 53. 47 5. 81 12. 05

Do Ethyl 150/0.1 mm. 64. 33 7. 32 16. 07 12. 26 64'. 35 7. 13 12. 08 3, 4-dimethylphenyl Methyl 177-79 61. 77 6. 47 18. 00 13. 74 62. 05 6. 40 13. 2, 4, 6-trimethylpheny1 do 78-79 63. 12 6. 92 16. 98 12. 96 63. 09 6. 96 16. 13. 08 4-methoxyphenyl do. 128-29 56. 14 5. 56 17. 85 13. 62 56. 25 5. 59 13. 60 3, 5-dimethoxyphenyl do 117-118 54. 32 5. 69 15. 83 12. 08 54. 22 5. 69 12. 07

Do Methyl HO 212-213 dec. 47. 75 5. 34 13. 92 10. 62 48. 02 5. 60 13. 11. 02 2-hydroxypheny M h 270-72 54. 27 5. 01 18. 98 14. 49 45. 77 5. 29 13. 48 4-Ditrophen 270-72 47. 99 4. 02 22. 38 47. 66 4. 38 2, fi-dichlorobe 141-43 45. 84 3. 84 14. 58 11. 12 45. 70 4. 01 11. 20 1-naphthyl 66-67 68. 05 5. 71 14. 68. 80 6. 11 15. 28

STRUCTURE AND PHYSICAL PROPERTIES OF 2-DIALKYLAMINO-fi-PHENYL-1,3,4-THIADIAZOLES (A1 15 PHENYL) R Analysis M.P. C.) or Calculated Found R mm.) C H Cl N S C H Cl N S Dimethylamino 97-99 58. 51 5. 40 20. 47 15. 62 58. 36 5. 01 20. 70 15- 59 D methylam no HCl-salt 198-200 49. 68 5. 00 14, 66 17. 38 13. 26 49. 14 5. 67 13. 80 16. 20 12. 68 Dimethylanuno, salt with C CIQCOIH Dimethylamino picrate 193-95 45. 93 3. 3 7. Ethyl methylamino 48-50 60. 24 5. 14.

Use of the oxadiazoles nd i diazol b' i a th a es as her 1c deg 50 The same rating schedule was employed to udge pre- So as to illustrate the useful herbicidal properties of the products of this novel method, a group of controlled greenhouse experiments is described below.

(1) Post emergent use: An aqueous dispersion of each active compound was prepared by combining 0.4 gram of the compound with about 4 ml. of a solvent-emulsifier mixture (3 parts of a commercial polyoxyethylated vegetable oil emulsifier, one part xylene, one part kerosene) and then adding water, with stirring, to a final volume of 40 ml.

The species of plants on which each compound was to be tested were planted in four-inch pots in a greenhouse. Ten to eighteen days after emergence of the plants, three pots were sprayed with an aqueous dispersion of the active compound prepared as described above, at a rate of 5 lbs. of active compound per acre and at aspray volume of 60 gallons per acre. Approximately one week after the spray application the plants 'were observed and the results rated according to the following schedule:

Type of action Degree C=chlorosis (bleaching) 0=no efiect. N=necrosis 1=slight efiect.

emergent results obtained according to the procedure below.

(2) Pre-emergent use: A solution of each active compound was prepared by dissolving 290 mg. of the compound to be tested in 200 ml. of acetone. Disposable paper trays about 2 inches deep and half the size of ordinary greenhouse flats were prepared and seeded with a variety of species of plant seeds, then sprayed with the acetone solution at the rate of 10 lbs. of active chemical per acre of sprayed area. One flat, which had been seeded with alfalfa, brome, flax, oats, radishes and sugar beets was held at 75 F. day temperature; another seeded with corn, coxcomb, cotton, crabgrass, millet and soybeans was held at F. Twenty-one days after seeding and treatment the flats were examined and herbicidal effect was rated according to the above schedule.

Both post-emergent and pre-emergent results are set forth in the following table.

ghum mate Soy- Cot- Al Rad- Sugar bean ton ialta Oats Corn Flax ish beet Wheat N4 Millet

Activity (preor post- Crab- Coxemergent) grass comb Brome {Post I Pre G3 N4 {Post Post Pre N3 N4 0 ;.-..-..{Post-.-......

LEM-OXADIAZOLEB AND 1,3,4-THIADLAZOLES WITH INTERESTING -8ELECTIVELY HERBICIDAL PROPERTIES Compound 2-(2,4'-diehlorophenyl)Mathylamlno-LBA- hmh 2-diethylamino-5-(2'-methylphenyl)-1,3,4-oxadiazol z'dlmethylamj110*5*(2"1110thylphenyl)-1,3,4n!m1imnln z-dimethylamino-li-(2-methylpheny1)-1,3,4-thiadiazo1e. z-dlethylamlnoe-(2'-methy1phenyl)-1,8,4- m 2-dimethylamino-5-(2,4'-dimethylphenyl)-1,3,4-thladlazole As can be seen from the tabulated data, the specifically exemplified herbicides have" interesting utility. Probably the most interesting use is for control of unwanted vegeta tion in soybeans, since the ability to do this is not common.

I claim:

1. The method of manufacturing a dialkylamino compound of the structural formula X 10 Al? N i L N in which X represents a heterocyclic atom selected from the group consisting of oxygen and sulfur, Ar, is an aromatic substituent and R and R are methyl or ethyl alkyl substituents comprising the steps,

(a) reacting a S-Substituted tetrazole of the structural formula with a compound of the formula X /R Cl N RI and 39 (b) heating the resulting reaction product at 90 to 130 C. to cause liberation of nitrogen and molecular arrangement.

2. The method of manufacturing 2-diethylamino-5-(2'- methylphenyl)-1,3,4-oxadiaz0le comprising the steps (a) reacting 5-(2'-methylphenyl)-tetrazole with N,N-

diethylcarbamyl chloride and (b) heating the resulting reaction product at 90 to 130 C. to cause liberation of nitrogen and molecular rearrangement.

40 3. The method of manufacturing Z-dimethylamino-S- (2-methylphenyl)-1,3,4-oxadiazole comprising the steps (a) reacting 5-(2'-methylphenyl)-tetrazole with N,N-

dimethylcarbamyl chloride and (b) heating the resulting reaction product at 90 to 130 C. to cause liberation of nitrogen and molecular rearrangement.

4. The method of manufacturing Z-dimethyIaminO-S- (2-methylphenyl)-1,3,4-thiadiazole comprising the steps (a) reacting 5-(2'-methylphenyl)-tetrazole with N,N-

dimethylthiocarbamyl chloride and (b) heating the resulting reaction product at 90 to 130 C. to cause liberation of nitrogen and molecular rearrangement. 5. The method of manufacturing 2-diethylamino-5-(2'- mcthylphenyl)-1,3,4-thiadiazole comprising the steps (a) reacting 5-(2-methylphenyl)-tetrazole with N,N-

diethylthiocarbamyl chloride and (b) heating the resulting reaction product at 90 to 130 C. to cause liberation of nitrogen and molecular re- 0 arrangement. 6. The method of manufacturing Z-dimethylamino-S- (2, -dimethy1phenyl)-l,3,4-thiadiazole comprising the steps (a) reacting 5 (2',4-dimethylphenyl)-tetraz0le with 55 N,N-dimethylthiocarba=myl chloride and (b) heating the resulting reaction product at 90 to 130 C. to cause liberation of nitrogen and molecular rearrangement.

References Cited Herbst, J. Org. Chem.,26, 2372-3 (1961).

RICHARD J. GALLAGHER, Primary Examiner US. 01. X.R 

